scholarly journals LRRK2 regulates innate immune responses and neuroinflammation during Mycobacterium tuberculosis infection

2019 ◽  
Author(s):  
C.G. Weindel ◽  
S.L. Bell ◽  
T.E. Huntington ◽  
K.J. Vail ◽  
R. Srinivasan ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Glial Cells ◽  
Mycobacterial Infection ◽  
Type I Interferons ◽  
Type I ◽  
Innate Immune Responses ◽  
Mycobacterium Tuberculosis Infection ◽  
Inflammatory Molecules ◽  
Multiple Hit ◽  
The Brain

SUMMARYDespite many connections between mutations in leucine-rich repeat kinase 2 (LRRK2) and susceptibility to mycobacterial infection, we know little about its function outside of the brain, where it is studied in the context of Parkinson’s Disease (PD). Here, we report that LRRK2 controls peripheral macrophages and brain-resident glial cells’ ability to respond to and express inflammatory molecules. LRRK2 KO macrophages express elevated basal levels of type I interferons, resulting from defective purine metabolism, mitochondrial damage, and engagement of mitochondrial DNA with the cGAS DNA sensing pathway. While LRRK2 KO mice can control Mycobacterium tuberculosis (Mtb) infection, they exhibit exacerbated lung inflammation and altered activation of glial cells in PD-relevant regions of the brain. These results directly implicate LRRK2 in peripheral immunity and support the “multiple-hit hypothesis” of neurodegenerative disease, whereby infection coupled with genetic defects in LRRK2 create an immune milieu that alters activation of glial cells and may trigger PD.

scholarly journals Mitochondria: powering the innate immune response to Mycobacterium tuberculosis infection

2021 ◽  
Author(s):  
Kristin L. Patrick ◽  
Robert O. Watson
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Immune Responses ◽  
Molecular Mechanisms ◽  
Bacterial Pathogen ◽  
Tuberculosis Patient ◽  
Innate Immune ◽  
Inflammasome Activation ◽  
Type I ◽  
Innate Immune Responses ◽  
Mycobacterium Tuberculosis Infection

Within the last decade, we have learned that damaged mitochondria activate many of the same innate immune pathways that evolved to sense and respond to intracellular pathogens. These shared responses include cytosolic nucleic acid sensing and type I interferon (IFN) expression, inflammasome activation that leads to pyroptosis, and selective autophagy (called mitophagy when mitochondria are the cargo). Because mitochondria were once bacteria, parallels between how cells respond to mitochondrial and bacterial ligands are not altogether surprising. However, the potential for crosstalk or synergy between bacteria- and mitochondria-driven innate immune responses during infection remains poorly understood. This interplay is particularly striking—and intriguing—in the context of infection with the intracellular bacterial pathogen Mycobacterium tuberculosis (Mtb). Multiple studies point to a role for Mtb infection and/or specific Mtb virulence factors in disrupting the mitochondrial network in macrophages leading to metabolic changes and triggering potent innate immune responses. Research from our labs and others argues that mutations in mitochondrial genes can exacerbate mycobacterial disease severity by hyper-activating innate responses or activating them at the wrong time. Indeed, growing evidence supports a model whereby different mitochondrial defects or mutations alter Mtb infection outcomes in distinct ways. By synthesizing the current literature in this minireview, we hope to gain insight into the molecular mechanisms driving, and consequences of, mitochondrial-dependent immune polarization so that we might better predict tuberculosis patient outcomes and develop host-directed therapeutics designed to correct these imbalances.

scholarly journals LRRK2 maintains mitochondrial homeostasis and regulates innate immune responses to Mycobacterium tuberculosis

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Chi G Weindel ◽  
Samantha L Bell ◽  
Krystal J Vail ◽  
Kelsi O West ◽  
Kristin L Patrick ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Mycobacterial Infection ◽  
Innate Immune ◽  
Type I ◽  
Immune Gene ◽  
Innate Immune Responses ◽  
Interferon Stimulated Genes ◽  
Mitochondrial Homeostasis ◽  
Mitochondrial Defects ◽  
Interferon Responses

The Parkinson’s disease (PD)-associated gene leucine-rich repeat kinase 2 (LRRK2) has been studied extensively in the brain. However, several studies have established that mutations in LRRK2 confer susceptibility to mycobacterial infection, suggesting LRRK2 also controls immunity. We demonstrate that loss of LRRK2 in macrophages induces elevated basal levels of type I interferon (IFN) and interferon stimulated genes (ISGs) and causes blunted interferon responses to mycobacterial pathogens and cytosolic nucleic acid agonists. Altered innate immune gene expression in Lrrk2 knockout (KO) macrophages is driven by a combination of mitochondrial stresses, including oxidative stress from low levels of purine metabolites and DRP1-dependent mitochondrial fragmentation. Together, these defects promote mtDNA leakage into the cytosol and chronic cGAS engagement. While Lrrk2 KO mice can control Mycobacterium tuberculosis (Mtb) replication, they have exacerbated inflammation and lower ISG expression in the lungs. These results demonstrate previously unappreciated consequences of LRRK2-dependent mitochondrial defects in controlling innate immune outcomes.

scholarly journals Accuracy of the QuantiFERON-TB Gold in Tube for diagnosing tuberculosis in a young pediatric population previously vaccinated with Bacille Calmette-Guerin

2014 ◽  
Vol 32 (1) ◽  
pp. 04-10 ◽  
Author(s):  
Marcelo Genofre Vallada ◽  
Thelma Suely Okay ◽  
Gilda Maria B. Del Negro ◽  
Claudio Amaral Antonio ◽  
Lidia Yamamoto ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Roc Curve ◽  
Pediatric Population ◽  
Area Under The Curve ◽  
Mycobacterial Infection ◽  
Tuberculosis Infection ◽  
Mycobacterium Tuberculosis Infection ◽  
Assay Sensitivity ◽  
Negative Results ◽  
Release Assay

Objective: To evaluate the accuracy of an interferongamma release assay (QuantiFERON-TB Gold in Tube) for diagnosing Mycobacterium tuberculosis infection in a young pediatric population. Methods: 195 children previously vaccinated with BCG were evaluated, being 184 healthy individuals with no clinical or epidemiological evidence of mycobacterial infection, and 11 with Mycobacterium tuberculosis infection, according to clinical, radiological, and laboratory parameters. A blood sample was obtained from each child and processed according to the manufacturer's instructions. The assay performance was evaluated by a Receiver Operating Characteristic (ROC) curve. Results: In the group of 184 non-infected children, 130 (70.6%) were under the age of four years (mean age of 35 months). In this group, 177 children (96.2%) had negative test results, six (3.2%) had indeterminate results, and one (0.5%) had a positive result. In the group of 11 infected children, the mean age was 58.5 months, and two of them (18%) had negative results. The ROC curve had an area under the curve of 0.88 (95%CI 0.82-0.92; p<0.001), disclosing a predictive positive value of 81.8% for the test (95%CI 46.3-97.4). The assay sensitivity was 81.8% (95%CI 48.2-97.2) and the specificity was 98.8% (95%CI 96-99.8). Conclusions: In the present study, the QuantiFERON-TB Gold in Tube performance for diagnosing M. tuberculosis infection was appropriate in a young pediatric population.

A very young patient with Tubercular Meningitis and its complications

2020 ◽  
Vol 10 (2) ◽  
pp. 400-401
Author(s):  
Rowshan Jahan Akhter ◽  
BH Nazma Yasmeen
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Cranial Nerve ◽  
Obstructive Hydrocephalus ◽  
Cns Infection ◽  
Communicating Hydrocephalus ◽  
Mycobacterium Tuberculosis Infection ◽  
Nerve Roots ◽  
Tubercular Meningitis ◽  
Medical College ◽  
The Brain

A case report on a successful management of an eight months old boy with Tubercular Meningitis with Multiple Tuberculoma in Brain with Obstructive Hydrocephalus with Left sided Lower motor neuron type Facial Palsy with Right Sided Hemiparesis. Tuberculous meningitis (TBM) is Mycobacterium tuberculosis infection of the Brain Meninges.1,2 In TBM inflammation occur mainly in the base of the brain and when the inflammation affect the brain stem subarachnoid area, cranial nerve roots then symptoms may occur like space-occupying lesions.3,4 TBM is more common in children than in adults, especially children aged 0-5 years.5 In children central nervous system tuberculosis usually presents as tubercular meningitis, post-tubercular meningitis hydrocephalus, and rarely a space-occupying lesions known as tuberculomas.6 TBM accounts for 2–5% of all active cases of Mycobacterium tuberculosis.7 Pulmonary infection coexists in 25–83% of TBM.8-10 Predominately primary CNS infection is found in children and leptomeningeal infection presents as meningitis, cranial nerve (CN) palsies (most commonly CN 2, 3, 4, and 7), and communicating hydrocephalus.11 Northern International Medical College Journal Vol.10 (2) Jan 2019: 400-401

scholarly journals RNA Sensing of Mycobacterium tuberculosis and Its Impact on TB Vaccination Strategies

Vaccines ◽  
2020 ◽  
Vol 8 (1) ◽  
pp. 67 ◽  
Author(s):  
Sanne Burkert ◽  
Ralf R. Schumann
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Type I Interferons ◽  
Immune Memory ◽  
Type I ◽  
Effective Prevention ◽  
Vaccination Strategies ◽  
Host Interaction ◽  
Global Threat ◽  
Antigen Presenting ◽  
The Impact

Tuberculosis (TB) is still an important global threat and although the causing organism has been discovered long ago, effective prevention strategies are lacking. Mycobacterium tuberculosis (MTB) is a unique pathogen with a complex host interaction. Understanding the immune responses upon infection with MTB is crucial for the development of new vaccination strategies and therapeutic targets for TB. Recently, it has been proposed that sensing bacterial nucleic acid in antigen-presenting cells via intracellular pattern recognition receptors (PRRs) is a central mechanism for initiating an effective host immune response. Here, we summarize key findings of the impact of mycobacterial RNA sensing for innate and adaptive host immunity after MTB infection, with emphasis on endosomal toll-like receptors (TLRs) and cytosolic sensors such as NLRP3 and RLRs, modulating T-cell differentiation through IL-12, IL-21, and type I interferons. Ultimately, these immunological pathways may impact immune memory and TB vaccine efficacy. The novel findings described here may change our current understanding of the host response to MTB and potentially impact clinical research, as well as future vaccination design. In this review, the current state of the art is summarized, and an outlook is given on how progress can be made.

scholarly journals cGAS/STING/TBK1/IRF3 Signaling Pathway Activates BMDCs Maturation Following Mycobacterium bovis Infection

2019 ◽  
Vol 20 (4) ◽  
pp. 895 ◽  
Author(s):  
Qiang Li ◽  
Chunfa Liu ◽  
Ruichao Yue ◽  
Saeed El-Ashram ◽  
Jie Wang ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Signaling Pathway ◽  
Mycobacterium Bovis ◽  
New Drugs ◽  
Type I Interferons ◽  
Type I ◽  
Type I Ifn ◽  
Innate Immune Responses ◽  
Dependent Signal

Cyclic GMP-AMP synthase (cGAS) is an important cytosolic DNA sensor that plays a crucial role in triggering STING-dependent signal and inducing type I interferons (IFNs). cGAS is important for intracellular bacterial recognition and innate immune responses. However, the regulating effect of the cGAS pathway for bone marrow-derived dendritic cells (BMDCs) during Mycobacterium bovis (M. bovis) infection is still unknown. We hypothesized that the maturation and activation of BMDCs were modulated by the cGAS/STING/TBK1/IRF3 signaling pathway. In this study, we found that M. bovis promoted phenotypic maturation and functional activation of BMDCs via the cGAS signaling pathway, with the type I IFN and its receptor (IFNAR) contributing. Additionally, we showed that the type I IFN pathway promoted CD4+ T cells’ proliferation with BMDC during M. bovis infection. Meanwhile, the related cytokines increased the expression involved in this signaling pathway. These data highlight the mechanism of the cGAS and type I IFN pathway in regulating the maturation and activation of BMDCs, emphasizing the important role of this signaling pathway and BMDCs against M. bovis. This study provides new insight into the interaction between cGAS and dendritic cells (DCs), which could be considered in the development of new drugs and vaccines against tuberculosis.

scholarly journals TRIM14 Is a Key Regulator of the Type I IFN Response during Mycobacterium tuberculosis Infection

2020 ◽  
Vol 205 (1) ◽  
pp. 153-167 ◽  
Author(s):  
Caitlyn T. Hoffpauir ◽  
Samantha L. Bell ◽  
Kelsi O. West ◽  
Tao Jing ◽  
Allison R. Wagner ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Tuberculosis Infection ◽  
Type I ◽  
Type I Ifn ◽  
Mycobacterium Tuberculosis Infection

scholarly journals Cytosolic DNA sensor-initiated innate immune responses in mouse ovarian granulosa cells

Reproduction ◽  
2017 ◽  
Vol 153 (6) ◽  
pp. 821-834 ◽  
Author(s):  
Keqin Yan ◽  
Dingqing Feng ◽  
Jing Liang ◽  
Qing Wang ◽  
Lin Deng ◽  
...  
Keyword(s):  
Immune Responses ◽  
Granulosa Cells ◽  
Innate Immune ◽  
Type I Interferons ◽  
Endocrine Function ◽  
Type I ◽  
Dna Sensor ◽  
Innate Immune Responses ◽  
Oligoadenylate Synthetase ◽  
Ovarian Granulosa Cells

Viral infections of the ovary may perturb ovarian functions. However, the mechanisms underlying innate immune responses in the ovary are poorly understood. The present study demonstrates that cytosolic viral DNA sensor signaling initiates the innate immune response in mouse ovarian granulosa cells and affects endocrine function. The cytosolic DNA sensors p204 and cGAS and their common signaling adaptor stimulator of interferon (IFN) genes (STING) were constitutively expressed in granulosa cells. Transfection with VACV70, a synthetic vaccinia virus (VACV) DNA analog, induced the expression of type I interferons (IFNA/B) and major inflammatory cytokines (TNFA and IL6) through IRF3 and NF-κB activation respectively. Moreover, several IFN-inducible antiviral proteins, including 2′,5′-oligoadenylate synthetase, IFN-stimulating gene 15 and Mx GTPase 1, were also induced by VACV70 transfection. The innate immune responses in granulosa cells were significantly reduced by the transfection of specific small-interfering RNAs targeting p204, cGas or Sting. Notably, the VACV70-triggered innate immune responses affected steroidogenesis in vivo and in vitro. The data presented in this study describe the mechanism underlying ovarian immune responses to viral infection.

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